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Fig 9. Schematic representation of the GPCR-G-protein-GIRK system.In resting state (no activated GPCR), the GIRK1/2 channel, a heterotetramer of 2 GIRK1 (grey) and 2 GIRK2 (green) subunits, is expected to interact with ~ 3–4 Gβγ subunits, two of which are bound to GαGDP subunits (GDP is shown by a yellow circle). For simplicity, the hypothetical Gβγ anchoring sites (which may be separate or partly overlapping with the Gβγ-activation sites) are not shown. The interaction of GIRK with Gβγ subunits is reversible. GαGDP can release the bound Gβγ in basal state, but since Gβγ-GαGDP interaction is of a high affinity, the probability of GIRK activation due to this process is relatively low. Thus, at any given time the channel is occupied by 2–3 Gβγ molecules (with an open probability of 6–26% of Po,max as shown in Fig 2C). GIRK overexpression leads to a decrease in GIRK:Gα ratio but does not change the GIRK:Gβγ ratio due to the additional recruitment of Gβγ by GIRK1/2, thus effectively increasing the proportion of channels occupied by > 3 Gβγ molecules, leading to an increase in “basal” open probability. The opposite process occurs upon overexpression of Gα, leading to a decrease in free Gβγ available for channel activation. On expression of Gβγ, its availability for channel activation increases, leading to higher fraction of 4 Gβγ-occupied channels with an open probability close to Po,max. Activation of G-proteins by an agonist (grey pentagon) via a GPCR (magenta) leads to an exchange of GDP to GTP (red circle) on Gα molecules, and to the subsequent dissociation of the Gαβγ heterotrimer, liberating additional Gβγ for channel activation. Image published in: Yakubovich D et al. (2015) Image reproduced on Xenbase with permission of the publisher and the copyright holder. This image is reproduced with permission of the journal and the copyright holder. This is an open-access article distributed under the terms of the Creative Commons Attribution license Larger Image Printer Friendly View

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